December 15, 2014

Drug Improves Function in Rats with Spinal Cord Injuries

At a Glance

  • Researchers developed a drug that allows spinal cord neurons in rats to grow after injury, improving movement and bladder function.
  • With further development, the approach may lead to treatments for paralysis from some spinal cord injuries and other conditions where scar tissue blocks nerve regeneration.
A chemical barrier. After spinal cord injury, a chemical barrier (dotted lines) blocks extension of nerve fibers. An experimental treatment enables nerves to cross this barrier (right). Jerry Silver lab, Case Western Reserve School of Medicine

Every year, tens of thousands of people nationwide are paralyzed by spinal cord injuries. These injuries crush and sever the long axons of spinal nerve cells, cutting off communication between the brain and the body and leading to paralysis.

After a spinal cord injury, axons are unable to regenerate, or sprout. The barrier to their regrowth is largely due to chemicals called chondroitin sulphate proteoglycans (CSPGs). CSPGs are known to play a role in stabilizing connections between nerve cells. After spinal cord injury, nervous system support cells called glia produce higher levels of CSPGs both in the injury region and throughout the spinal cord.

Recent studies have revealed that CSPGs stop axon growth by interacting with a receptor protein found in axons called protein tyrosine phosphatase sigma (PTPσ). Dr. Bradley Lang at Case Western Reserve University School of Medicine came up with the idea of designing a drug that would help axons regenerate by inhibiting PTPσ. The research, led by Dr. Jerry Silver and published online on December 3, 2014, in Nature, was partially funded by NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

The team first identified a part of the PTPσ protein called a wedge domain. Wedge domains have been shown to regulate the activity of receptor phosphatases. The scientists developed a molecule that mimicked the shape of the PTPσ wedge domain but that could easily cross cell membranes to spread through nervous system cells.

The drug, which they call intracellular sigma peptide (ISP), successfully bound both human and rodent PTPσ. Neurons grown in a Petri dish with CSPGs were able to extend axons to a much greater extent when treated with ISP.

Next, the researchers tested the drug in rats with spinal cord injuries. After confirming that the drug was able to enter the rat nervous system, they tested it in injured animals. The scientists injected ISP or a placebo under the skin near the site of injury once daily for 7 weeks. After several weeks, the rats given ISP showed significant improvement in movement and/or bladder function, while the placebo treatment had no effect.

ISP caused sprouting of new axons that use the neurochemical serotonin to communicate. Blocking serotonin communication with a drug partially reversed the beneficial effects of the ISP injections, suggesting that those new axons—and, by extension, the ISP compound—were responsible for the rats’ recovery.

“Our goal is to progress this treatment forward for use as a therapeutic following spinal cord injury,” Lang says. The team is now planning to test the drug in preclinical trials as well as in rodent models of heart attack, peripheral nerve injury, and multiple sclerosis.

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Reference:  Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury. Lang BT, Cregg JM, DePaul MA, Tran AP, Xu K, Dyck, SM, Madalena KM, Brown BP, Weng YL, Li S, Karimi-Abdolrezaee S, Busch SA, Shen Y, Silver J. Nature, 2014 Dec 3. doi: 10.1038/nature13974. [Epub ahead of print]. PMID: 25470046.

Funding: NIH’s National Institute of Neurological Disorders and Stroke (NINDS); Case Western Reserve University Council to Advance Human Health; P. Jing, R. Senior, and S. Poon; Unite to Fight Paralysis; the Brumagin Memorial Fund; Spinal Cord Injury Sucks; United Paralysis Foundation; and The Kaneko Family Fund.